Age-related macular degeneration (AMD) causes irreversible central visual loss in the aged population worldwide. Various studies suggest that AMD has a significant genetic component. Current evidence supports the hypothesis that gene variation creates a predisposition to the disease. In 2003, we initiated this project by recruiting advanced AMD patients and age-matched control individuals with normal retinas. Up to date, 465 individuals have been enrolled and 107 histopathological cases with AMD have been collected. We continue to analyz 835 DNA samples from the Blue Mountain Eye Study in Australia and 534 DNA samples from the AREDS project in USA. We have compared the allelic frequencies of single nucleotide polymorphisms (SNPs) within candidate genes between AMD and control subjects, followed by functional studies of these SNPs by in vitro and/or in vivo experiments. Through this approach, we have identified genetic risk factors of AMD and the possible roles of these gene variations in the pathogenesis of the disease. Based on the information obtained from the above approaches, a genetically engineered animal (Ccl2/Cx3cr1 double deficiencies on rd8 background (DKO rd8) mice) was generated to act as an AMD model in 2007. In FY2012, (1) we signed 2 additional material transfer agreements with 2 other extramural research institutes and transferred living DKO rd8 mice to them for collaborative studies of mechanisms and therapeutic options; (2) we continued characterizing DKO rd8 mice, a paper of 3D optical coherence tomography assessment (collaboration with Dr. Nicholas Bazan) was published (Zhou, et al. Exp Eye Res 2011;93:636-648); (3) we evaluated the anti-inflammatory and suppressive effect of TSG-6 recombinant protein (collaboration with Dr. Prockop) on the retinal lesions and published a paper (Tuo, et al. Neuroinflammation 2012;9:59). Currently, we are evaluating other compounds such as PDGF-CC (collaboration with Dr. Xuri Li), PEDF (collaboration with Dr. Becerra) and STC-1 (continue collaboration with Dr. Prockop) by using this animal model; (4) we provided DKO rd8 retina to collaborators for studies on microarray (collaboration with Dr. Mengqing Xiang and microRNA involvements in AMD (collaboration with Dr. Shusheng Wang); (5) using paraffin-embeded, archived slides, we studied the role of macrophage polarization in AMD and published our results (Cao, et al. Pathol Int 2011;61:528-535); (6) we conducted a pharmacogenomic study (collaboration with Drs. Catherine Meyerle, Richard Rosen and Shree Kurup) on the efficacy of anti-VEGF therapy on AMD and patients genotypes and currently have the manuscript under review in Molecular Vision; (7) we performed a large scale SNP association study on the role of TIMP3 in AMD and have the manuscript under review in Eur J Hum Genet; (8) we published a review paper on the genetics of inflammation in AMD (Tuo, et al. Ocul Immunol Inflamm 2012;20:27-36) and a chapter regarding the role of oxidative stress in DKO rd8 mice (Tuo. Chapt 17 in Studies on Retinal and Choroidal Disorders (Stratton, Hauswirth, Gardner, eds.) Humana Press, 2012, pp. 355-365).